Numerous diseases are associated with degenerative changes in joint cartilage or misguided differentiation processes in bone marrow. Diseases of the muscle-skeletal system represent the third most cost intensive factor in treatment of diseases in Germany, after diseases of the cardio vascular system and diseases of the digestive system. One of the prerequisites for successful treatment of such diseases is the understanding of the cellular processes in the bone marrow that underlie these diseases or are associated therewith. So it is possible to treat e.g., leukaemia by replacement of the hematopoietic system of a patient. Also autoimmune diseases, like rheumatoid arthritis or lupus erythematodes, are, however, regulated by long-lived plasma and memory-T-cells which reside in specialized niches of the bone marrow.
The bone marrow is a multi-functional, multi-cellular tissue which, inter alia, is located in the lumen of long bones. The tissue develops during the embryonic development around month 4, in the context of the endochondral ossification, the development of the long bones. The bone marrow is characterized by a porous structure formed of cancellous bone and specialized connective tissue pervaded with numerous thin-walled blood vessels, the bone marrow sinusoids. One of the main functions of the bone marrow is the provision of a suitable environment for differentiation of the blood forming cells of the hematopoietic system. The hematopoietic stem cell (HSC) represents the starting point for these differentiation processes, wherein the hematopoietic stem cell resides in undifferentiated state in the hematopoietic stem cell niches in the cancellous bone structures of the bone marrow. The hematopoietic stem cell niches are divided in two functionally different subtypes. In the osteoblast-niche, the hematopoietic HSCs interact with specialized osteoblasts via different adhesion and signalling molecules whereby the HSCs are kept in a rounded, non-proliferating state. Upon mobilisation of HSCs, the stem cells migrate to the vascular stem cell niches located at the sinusoids where the HSCs exhibit increased proliferation. According to today's understanding of hematopoietic stem cell niches in bone marrow, the smallest unit of a stem cell niche system is formed of a combination of an osteoblast niche and a vascular niche located at a sinusoid blood vessel of cancellous bone. Apart from the functional structures of the stem cell niches, current research discloses bone marrow as home of the immunologic memory. Mesenchymal stroma cells (MSC) serve as cellular building blocks of survival niches for plasma and memory-T-cells. In summary, the biological functionality of the bone marrow depends on a number of cells like HSC, MSC, endothelial cells and osteoblasts and their proper interaction in the spatial compartment.
Hyaline cartilage of the joints, due to its properties of a high elasticity to pressure and a very even surface, allows for a friction-poor movement of the joints. The main part of this tissue is formed of a plurality of extracellular matrix proteins, whereas the cellular component, the chondrocytes, is embedded sparsely in this matrix either separately or in small groups (chondron). The lack of nerve fibres and blood vessels and the resulting low supply of the tissue with oxygen and nutrients generate a unique micro-environment for the chondrocytes. The cartilage tissue can be classified in multiple layers, wherein, due to the horizontal orientation of the matrix molecules, the uppermost layer can counteract friction and, due to the vertical orientation, the subjacent middle and lower layers can absorb impact force originating from movement. Although chondrocytes emerge early during endochondral ossification of the initial process of mesenchymal condensation and these cells contribute significantly to bone growth during epiphysis, the hyaline cartilage tissue in the joint develops only at a very late point in time during embryogenesis. Fully differentiated, fully functional layers of cartilage are formed only postnatal by beginning mechanical stimulation of the tissue. In the adult organism, homeostasis of cartilage tissue is highly dependent of the kind and strength of mechanic load and of the micro-environment of the embedded chondrocytes.
Numerous attempts have been made to develop and provide in vitro models and test systems for bone and cartilage tissue. These approaches are, however, directed either to the separated provision of bone or cartilage tissue. These models thus do represent the natural environment only partially and insufficiently in which development and homeostasis of bone, bone marrow and cartilage tissue takes place.